Despite improvements in the nutritional management of low birth weight infants and early weaned pigs, many experience growth faltering and this can incur both short- and long-term costs in terms of metabolic health and productivity. Our long-term goal is to identify strategies to optimize the nutritional management of both the human infant and the young pig whose growth has been compromised. The objective of this application is to determine whether the use of an oral leucine supplement can be used to enhance lean growth in early life when the intakes of protein and/or energy are marginal. The central hypothesis is that leucine supplementation stimulates the signaling pathways that regulate protein synthesis and satellite cell replication and inhibit protein degradation during early life, and these effects enhance lean growth when sustained over the long-term. The hypothesis is based on data from the applicants' laboratories. The rationale is that understanding the fundamental mechanisms by which leucine modulates lean body mass during early life has the potential to translate into practices that will improve lean growth of low birth weight infants and early weaned piglets. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine whether prolonged leucine supplementation of a marginal protein diet enhances lean mass by up-regulating protein synthesis and myonuclear accretion and down-regulating protein degradation, and also determine whether this response requires the addition of other branched-chain amino acids; and 2) Determine if supplementation with leucine, or leucine and additional branched chain amino acids, of a diet that is marginally restricted in both protein and energy will enhance lean mass accretion, and to identify the mechanisms involved. We will determine body composition, growth rate, feed efficiency, protein synthesis and degradation rates, satellite cell abundance and proliferative capacity, amino acid signaling to translation, degradation signaling, and amino acid oxidation in young pigs fed for 10 d leucine or branched-chain amino acid supplemented diets that are marginally (80%) restricted in protein (Aim 1) or protein and energy (Aim 2). The methods are well-established in the applicants' laboratories. The approach is innovative, because it will examine the coordinated response of muscle protein synthesis, protein degradation, and myonuclear accretion to long-term leucine supplementation during early life and determine the impact on lean growth. The proposed work is unique because it is the first to comprehensively examine the coordinated regulation of all the component processes that determine muscle growth. The proposed research is significant, because it is expected to advance our understanding of the role of leucine in the regulation of lean growth in early life. The results will provide important novel information on the potential for using leucine supplementation to optimize the nutritional management of low birth weight infants, and to improve the efficiency of utilization of dietary nutrients for pork production. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the discovery of the mechanisms by which leucine influences lean growth in neonates is expected to bring basic research closer to the translational level of improving the nutritional support of low birth weight infants as well as the efficiency of utilization of dietary nutrients fr pork production. Thus, the proposed research using an agriculturally important domestic species is relevant to the missions of the NIH and USDA as it will provide fundamental new knowledge that has dual benefits relevant for the improvement of human health and food animal production.